Overall objectives are a better definition of the origin, nature, regulation and effects of Big Renin in human plasma. We have partially purified Big Renin from plasma, amniotic fluid and kidney homogenates, and have demonstrated similar enzymatic and immunologic characteristics, but differences in apparent molecular weight. We are testing the effects of cathepsins present in tissue homogenates on the size and activity of renin. We are studying acid proteases which co-purify with renin and interfere with its measurement and characterization. These studies are important in extracting, detecting and purifying renin from other tissues (arterial wall, adrenal cortex) in which renin-like enzymes have been found. We plan further studies of the effects of non-steroidal anti-inflammatory drugs on plasma active and inactive renins, as well as specific investigations of associated clinically important disturbances of adrenal and kidney functions and electrolyte balance (hyperkalemia). The effects of changing from a chronic hyperglycemic state to euglycemia on kidney function, proteinuria, and plasma renins will be measured in diabetic volunteers. Glycosylation of hemoglobin and renin will be monitored in this study. Non-steroidal anti-inflammatory drugs depress active renin in plasma, with effects on inactive renin, aldosterone secretion, and plasma potassium which vary from negligible to clinically significant hyperkalemia. The effects of mineralocorticoids and diuretics, alone or in combination, will be tested. The proposed studies will provide new information; clinical results are directly applicable to improved patient care.